title: High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring.
abstract: Excess vitamins, especially folate, are consumed during pregnancy but later-life effects on the offspring are unknown. High multivitamin (10-fold AIN-93G, HV) gestational diets increase characteristics of metabolic syndrome in Wistar rat offspring. We hypothesized that folate, the vitamin active in DNA methylation, accounts for these effects through epigenetic modification of food intake regulatory genes. Male offspring of dams fed 10-fold folate (HFol) diet during pregnancy and weaned to recommended vitamin (RV) or HFol diets were compared with those born to RV dams and weaned to RV diet for 29 weeks. Food intake and body weight were highest in offspring of HFol dams fed the RV diet. In contrast, the HFol pup diet in offspring of HFol dams reduced food intake (7%, p = 0.02), body weight (9%, p = 0.03) and glucose response to a glucose load (21%, p = 0.02), and improved glucose response to an insulin load (20%, p = 0.009). HFol alone in either gestational or pup diet modified gene expression of feeding-related neuropeptides. Hypomethylation of the pro-opiomelanocortin (POMC) promoter occurred with the HFol pup diet. POMC-specific methylation was positively associated with glucose response to a glucose load (r = 0.7, p = 0.03). In conclusion, the obesogenic phenotype of offspring from dams fed the HFol gestational diet can be corrected by feeding them a HFol diet. Our work is novel in showing post-weaning epigenetic plasticity of the hypothalamus and that in utero programming by vitamin gestational diets can be modified by vitamin content of the pup diet.
authors.affiliation: Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Clara E
authors.initials: CE
authors.lastname: Cho
authors.forename: Diana
authors.initials: D
authors.lastname: Sánchez-Hernández
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Reza-López
authors.forename: Pedro S P
authors.initials: PS
authors.lastname: Huot
authors.forename: Young-In
authors.initials: YI
authors.lastname: Kim
authors.forename: G Harvey
authors.initials: GH
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D004032:Diet; D005247:Feeding Behavior / Q000187:drug effects*; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000235:genetics; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism; D014886:Weaning
chemical_list: D001786:Blood Glucose; D019208:Brain-Derived Neurotrophic Factor; D009478:Neuropeptide Y; D011985:Receptors, Serotonin; D011333:Pro-Opiomelanocortin; D005492:Folic Acid
keywords: DNA methylation; folate; gene expression; gestation; glucose response; hypothalamus; obesity; post-weaning